Vitamin D3 Inhibition of Hedgehog Signaling and Cancer Chemoprevention

维生素 D3 抑制 Hedgehog 信号传导和癌症化学预防

• 批准号: 8544180
• 负责人: Ervin HAROLD Epstein
• 金额: $ 30.37万
• 依托单位: CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-12 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8544180
• 关键词: Address; Affect; Basal cell carcinoma; Chemoprevention; Chemopreventive Agent; Cholecalciferol; Colon; Cutaneous; Data; Dermatologist; Development; Diet; Dose; Epidemiology; Foundations; Frequencies; Future; Goals; Human; Intake; Investigation; Laboratory mice; Link; Maintenance; Malignant Neoplasms; Modeling; Mus; Mutation; Oral; Patients; Persons; Population; Production; Recommendation; Relative (related person); Relative Risks; Resistance; Risk; Role; Safety; Sampling; Series; Signal Transduction; Site; Sunlight; The Sun; UV induced; Ultraviolet Rays; Variant; Vitamin D; cancer chemoprevention; cancer risk; carcinogenesis; expectation; mortality; mouse model; public health relevance; restraint; skin cancer prevention; skin squamous cell carcinoma; smoothened signaling pathway; tool; tumor

DESCRIPTION (provided by applicant): Our goal in this Project is the elucidation of the role of the recently described inhibition of hedghog signaling by vitamin D3 as a mechanism underlying latitudinal variation in cancer mortality. Such variation has been known for nearly 70 years, and a prime role for sunlight-produced vitamin D stores has been postulated to be the mechanistic connection for three decades. Nonetheless, definitive proof linking increased vitamin D stores and reduction in relative risk of cancer remains elusive. Basal cell carcinomas (BCCs) are an ideal tumor in which to study this connection since aberrant hedghog signaling is pivotal to their development and maintenance, there are epidemiologic findings consistent with a role of ultraviolet radiation not only in their genesis but also in their restraint, and formidable tools now are available for their study. We will integrate both laboratory mouse models and human samples to address this question. Specifically we (i) will compare the effects of topical vs. oral vitamin D3 on BCC carcinogenesis in Ptch1 mice in which Cyp27B1 can be conditionally deleted, thus building on our preliminary data indicating that hedghog inhibition by topical D3 inhibits experimental murine BCC carcinogensis (ii) will compare the relative proportions of BCCs that are resistant to vitamin D3 inhibtion in the North vs. in the South in expectation that the proportion of vitamin D3-resistant BCCs will be higher in patients exposed to more sunlight and (iii) will compare UV-induced vitamin D3 production in subjects who have had BCCs with such production in persons who have had skin squamous cell carcinomas. Overall we expect that these studies will provide data making a compelling case for the conducting of a formal human trial of the anti-basal cell carcinoma chemopreventive efficacy of topical vitamin D3 and will form the foundation and template for extending these studies into extra-cutaneous tumors such as those of the colon, for which evidence is good for both a latitudinal gradient and a pathophysiologic role for hedgehog signaling. This Study is particularly germane now because growing concern that Dermatologists' relentless recommendations for sun avoidance to prevent skin cancers may be increasing the relative risk of extracutaneous cancers and because of the gathering momentum to increase the recommended daily vitamin D intake for the enitire population in unproved hopes that oral vitamin D supplements will convert the cancer risk of Minnesotans to that of Arizonans. Thus there is urgent need for further investigation into the relation of vitamin D3 to cancer risk.

描述（由申请人提供）：我们本项目的目标是阐明最近描述的维生素 D3 对 hedghog 信号传导的抑制作用，作为癌症死亡率纬度差异的潜在机制。近 70 年前人们就知道这种变异，并且 30 年来人们一直认为阳光产生的维生素 D 储备的主要作用是这种机械连接。尽管如此，将维生素 D 储存量增加与癌症相对风险降低联系起来的明确证据仍然难以捉摸。基底细胞癌 (BCC) 是研究这种联系的理想肿瘤，因为异常的 hedgehog 信号传导对其发展和维持至关重要，流行病学研究结果与紫外线辐射不仅在其发生中而且在其抑制中的作用一致，现在他们的研究已经有了强大的工具。我们将整合实验室小鼠模型和人类样本来解决这个问题。具体来说，我们 (i) 将比较外用维生素 D3 与口服维生素 D3 对可条件性删除 Cyp27B1 的 Ptch1 小鼠 BCC 致癌作用的影响，从而以我们的初步数据为基础，表明外用 D3 抑制 hedgehog 可抑制实验性小鼠 BCC 致癌作用 (ii) ）将比较北方与南方对维生素 D3 抑制具有抵抗力的 BCC 的相对比例，期望对维生素 D3 具有抵抗力的 BCC 比例暴露在更多阳光下的患者的 BCC 会更高，并且 (iii) 将患有 BCC 的受试者中紫外线诱导的维生素 D3 生成量与患有皮肤鳞状细胞癌的受试者中的维生素 D3 生成量进行比较。总体而言，我们预计这些研究将为开展局部维生素 D3 的抗基底细胞癌化学预防功效的正式人体试验提供令人信服的数据，并将为将这些研究扩展到皮外肿瘤奠定基础和模板例如结肠，其证据对于刺猬信号传导的纬度梯度和病理生理作用都是有利的。这项研究现在尤为重要，因为人们越来越担心皮肤科医生为预防皮肤癌而不断提出的避免日晒的建议可能会增加患皮外癌的相对风险，而且在未经证实的情况下，增加全民每日维生素 D 推荐摄入量的势头正在增强。希望口服维生素 D 补充剂能够将明尼苏达人的癌症风险降低到亚利桑那州人的癌症风险。因此，迫切需要进一步研究维生素 D3 与癌症风险的关系。